ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.377A>T (p.His126Leu) (rs144603589)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215363 SCV000273856 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000160946 SCV000211653 uncertain significance not provided 2014-06-12 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.377A>T at the cDNA level, p.His126Leu (H126L) at the protein level, and results in the change of a Histidine to a Leucine (CAT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D His126Leu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Histidine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51D His126Leu occurs at a position that is moderately conserved across species and is not located in a known functional domain. In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether RAD51D His126Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000802789 SCV000942633 uncertain significance Breast-ovarian cancer, familial 4 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 126 of the RAD51D protein (p.His126Leu). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is present in population databases (rs144603589, ExAC 0.001%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 182857). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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